Quaternary ammonium salts of omega-aminoalkylamides of r-2-aryl-propionic acids and pharmaceutical compositions containing them

ABSTRACT

(R)-Enantiomers of quaternary ammonium salts of general formula (I) are described:  
                 
 
     where R, R 1 , R 2 , R 3 , X and Z are as defined in the description.  
     The process for their preparation and pharmaceutical preparations thereof are also described.  
     The quaternary salts of the invention are useful in the inhibition of chemotaxis of neutrophils and monocytes induced by the fraction C 5 a of the complement and are used in the treatment of psoriasis, pemphigus and pemphigoid, rheumatoid arthritis, intestinal chronic inflammatory pathologies including ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonary disease and glomerulonephritis.  
     The compounds of the invention are advantageously used in the prevention and the treatment of injury caused by ischemia and reperfusion.

INTRODUCTION AND BACKGROUND OF THE INVENTION

[0001] The present invention relates to compounds useful in theinhibition of the chemotactic activation induced by the fraction C5a ofcomplement and from other chemotactic proteins (chemokines) that exerttheir action by activating a 7-transmembrane-domain (7-TM) receptor.Said compounds are quaternary ammonium salts of R-2-arylpropionamidesuseful in the treatment of pathologies depending on the chemotacticactivation of neutrophils and monocytes induced by the fraction C5a ofthe complement. In particular, the compounds of the invention are usefulin the treatment of psoriasis, rheumatoid arthritis, ulcerative colitis,acute respiratory distress syndrome, idiopathic fibrosis,glomerulonephritis and in the prevention of injury caused by ischemiaand reperfusion.

DETAILED DESCRIPTION OF THE INVENTION

[0002] The present invention relates to (R)-2-aryl-propionamides offormula (I):

[0003] wherein

[0004] Ar represents a substituted or non-substituted aryl group;

[0005] R represents hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,optionally substituted by a CO₂R₄ group, wherein R₄ represents hydrogenor a linear or branched C₁-C₆ alkyl group or a linear or branched C₂-C₆alkenyl group;

[0006] X represents:

[0007] linear or branched C₁-C₆ alkylene, C₄-C₆ alkenylene, C₄-C₆alkynylene, optionally substituted by a CO₂R₄ group or by a CONHR₅ groupwherein R₅ represents hydrogen, linear or branched C₂-C₆ alkyl or an OR₄group, R₄ being defined as above;

[0008] phenyl or a phenylmethylene group of formula:

[0009] a (CH₂)_(m)-B-(CH₂)_(n), group, optionally substituted by a CO₂R₄or CONHR₅ group, as defined above, wherein B is an oxygen or sulfuratom, m is zero or an integer from 2 to 3 and n is an integer from 2 to3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n isan integer from 2 to 3;

[0010] or X together with the nitrogen atom to which it is bound andwith the R₁ group forms a nitrogen containing 3-7 membered heterocyclicmonocyclic or polycyclic ring;

[0011] R₁, R₂ and R₃ are independently linear or branched C₁-C₆ alkyl,optionally substituted by an oxygen or sulfur atom, a C₃-C₇ cycloalkyl,C₃-C₆ alkenyl, C₃-C₆-alkynyl, aryl, aryl-C₁-C₃-alkyl,hydroxy-C₂-C₃-alkyl group;

[0012] or R₁ and R₂ together with the N atom to which they are bound,form a nitrogen containing -3-7 membered heterocyclic ring of formula(II) and R3 independently has the meanings as defined above.

[0013] In the general formula (II)

[0014] Y represents a single bond, a methylene group, an oxygen atom, anitrogen atom or a sulfur atom

[0015] p represents an integer from 0 to 3;

[0016] Z represents conventional anions used as counter-ions ofquaternary ammonium salts which are pharmaceutically acceptable, suchas, for example, halide ions Cl⁻, I⁻, Br⁻, the sulfate anion or anionsderived from sulfonic acids such as methansulfonate orp-toluensulfonate.

[0017] In the compounds of general formula (I), the aryl group Ar ispreferably chosen among:

[0018] a) an Ar_(a) mono- or poly-substituted aryl group, of the mostcommon (±) 2-aryl-propionic acids in current therapeutic use:alminoprofen, benoxaprofen, carprofen, fenbufen, fenoprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, R-naproxen,pirprofen and its dehydro and dihydro derivatives, pranoprofen,surprofen, tiaprofenic acid, zaltoprofen;

[0019] b) an aryl-hydroxymethyl-aryl group of formula (IIIa) both asdiastereoisomer mixture, or as single diastereoisomers,

[0020] wherein, when Ar₂ is phenyl Ar₁ is selected from the groupconsisting of phenyl and thien-2-yl while when Ar₁ is phenyl, Ar₂ isselected from the group consisting of phenyl, 4-thienyl, pyridyl.

[0021] c) an aryl of formula (IIIb):

[0022] wherein:

[0023] Ar_(b) is a phenyl mono- or poly-substituted by hydroxy,mercapto, C₁-C₃-alcoxy, C₁-C₃-alkylthio, chlorine, fluorine,trifluoromethyl, nitro, amino, optionally substituted C₁-C₇-acylamino;

[0024] Φ is hydrogen; a linear or branched C₁-C₅ alkyl, C₂-C₅-alkenyl orC₂-C₅-alkynyl residue optionally substituted by C₁-C₃-alkoxycarbonyl,substituted or non-substituted phenyl, 2-, 3- or 4-pyridyl,quinolin-2-yl; a C₃-C₆-cycloalkyl; 2-furyl; 3-tetrahydrofuryl;2-thiophenyl; 2-tetrahydrothiophenyl or a C₁-C₈-(alkanoyl,cycloalkanoyl, arylalkanoyl)-C₁-C₅-alkylamino group e.g.acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino;

[0025] d) a 2-(phenylamino)-phenyl of formula (IIIc):

[0026] wherein the substituents P₁ and P₂ indicate that the two phenylgroups bear, each independently, mono- or poly-substitutions withC₁-C₄-alkyl, C₁-C₃-alcoxy groups, chlorine, fluorine and/ortrifluoromethyl.

[0027] Preferred compounds according to the invention are those wherein:

[0028] R is hydrogen;

[0029] X is:

[0030] a linear C₁-C₆ alkylene, preferably C₂-C₄, optionally substitutedat C₁ by a —CO₂R₄ group as defined above;

[0031] a linear C₁-C₆ alkylene optionally substituted at C₁ by a —CONHR₅group wherein R₅ is OH;

[0032] 2-butynylene, cis-2-butenylene, trans-2-butenylene;

[0033] 3-oxa-pentylene, 3-thio-pentylene, 3-oxa-hexylene,3-thio-hexylene;

[0034] (CH₂)_(m)—CO—NH—(CH₂)_(n)— wherein m and n are each independentlyan integer from 2 to 3;

[0035] (CHR′)—CONH—(CH₂)_(n) wherein n is an integer from 2 to 3 and R′is a methyl, having absolute configuration R or S;

[0036] a phenyl or phenylmethylene group of formula:

[0037] or X, together with the N atom, form an azocycloaliphatic ring,preferably 1-methyl-piperidin-4-yl or 1,5-tropan-3-yl;

[0038] Preferred compounds are, in addition, those wherein the NR₁R₂R₃group represents a trimethylammonium, triethylammonium,N-methyl-N,N-diethylammonium, N-methyl-N,N-diisopropylammonium,N-cyclohexylmethyl-N,N-dimethylammonium,N-cyclopentylamino-N,N-dimethylammonium, N-methyl-1-piperidinium,N-ethyl-1-piperidinium, N-methyl-4-morpholinium,N-methyl-4thiomorpholinium, N-benzyl-N,N-dimethylammonium,N-allyl-1-piperidinium, 4-oxy-N-methyl-piperidinium group.

[0039] Examples of particularly preferred aryl groups comprise:4-isobutylphenyl, 4-cyclohexylmethylphenyl, 4-(2-methyl)allyl-phenyl,3-phenoxyphenyl, 3-benzoyl-phenyl, 3-acetyl-phenyl, the single (R) (S)diastereoisomers and the diastereoisomeric (R,S) mixture of3-C₆H₅—CH(OH)-phenyl, 3-CH₃—CH(OH)-phenyl, 5-C₆H₅—CH(OH)-thienyl,4-thienyl-CH(OH)-phenyl, 3-(pyrid-3-yl)-CH(OH)-phenyl,5-benzoyl-thien-2-yl, 4-thienoyl-phenyl, 3-nicotinoyl-phenyl,2-fluoro-4-phenyl, 6-metoxy-2-naphthyl, 5-benzoyl-2-acetoxy-phenyl,5-benzoyl-2-hydroxy-phenyl, 4-cyclopentyl-phenyl,4-(2-oxo-cyclopentyl)-phenyl, 4-(2-oxo-cyclohexyl)-phenyl.

[0040] Particularly preferred aryl groups of formula (III b) are phenylgroups 3-substituted by: isoprop-1-en-1-yl, isopropyl, pent-2-en-3-yl;pent-3-yl; 1-phenylethylen-1-yl; α-methylbenzyl.

[0041] Particularly preferred aryls of formula (III c) are:2-(2,6-dichloro-phenyl-amino)-phenyl;2-(2,6-dichloro-phenyl-amino)-5-chloro-phenyl;2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl;2-(3-trifluoromethyl-phenyl-amino)-phenyl. Examples of P₂ substitutedphenyl groups comprise phenyl groups substituted by one to three halogenatoms, C₁-C₄ alkyl groups, methoxy, trifluoromethyl, nitro, cyano,haloalkoxy.

[0042] Particularly preferred compounds of the invention are:

[0043](R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-trimethylammoniumiodide;

[0044](R)-{3-[2-(3-benzoylphenyl)-propionylamino]propyl}-trimethylammoniumiodide;

[0045](R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-N-ethyl-N,N-dimethylammoniumiodide;

[0046](R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-N-cyclohexylmethylN,N-dimethylammonium iodide;

[0047](R)-{3-[2-(4-cyclopentylmethylphenyl)-propionylamino]propyl}-trimethylammoniumiodide;

[0048](R)-{3-[2-(3-benzoylphenyl)-propionylamino]propyl}-N-isopropyl-N,N-dimethylammoniumiodide;

[0049](R)-{3-[2-(4-isobutylphenyl)-propionylamino]butyl-trimethylammoniumiodide;

[0050](R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-1-methyl-piperidiniumiodide;

[0051] (R)-{3-[2-(3-benzoylphenyl)-propionylamino]propyl}-1-methylpiperidinium iodide;

[0052](R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-4-methyl-morpholiniumiodide;

[0053](R)-{3-[2-(3-isopropylphenyl)-propionylamino]propyl}-4-methyl-thiomorpholiniummethanesulfonate;

[0054](R)-{3-[2-(4-isobutylphenyl)-propionylamino]ethyl-trimethylammoniumbromide;

[0055](R)-2-[(4-isobutylphenyl)-propionylamino]-1,1-dimethyl)piperidiniump-toluenesulfonate;

[0056](R),(S′)-2-(4-isobutylphenyl)-N-[(1-carboxy-2″-N,N,N-trimethylammonium)ethyl]propionamide methanesulfonate;

[0057] R(−)-2-[(4-isobutylphenyl)-N-(trimethylammoniumethyl)methylamide]propionamide iodide;

[0058](R)(3-{2-[2(2,6-dichlorophenylamino)-phenyl]-propionylamino}-propyl)-trimethylammoniummethanesulfonate;

[0059] (2R), (4″S)1-{4-carboxy-4-[2-(4-isobutyl-phenyl)-propionylamino]butyl}-1-methyl-piperidiniumiodide;

[0060]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(N-benzyl)-N,N-dimethylammoniumiodide;

[0061] 2R-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(1″methyl-4″carboxyamide) piperidinium iodide;

[0062](2R)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(1″-methyl-4″carbonyl) piperidinium iodide;

[0063]R(−)-{3,-[-(4′-isobutylphenyl)-propionylamino]-propyl}-triethylammoniumiodide;

[0064]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-1-allylpiperidiniumbromide;

[0065]R(−)-2-[(4′-isobutyl)phenyl]-N-[4″-N,N,N-trimethylaminophenyl]propionamideiodide;

[0066]R(−)-2-[(4′-isobutyl)phenyl]-N-[4″-N,N,N-trimethylaminomethylphenyl]propionamideiodide.

[0067] Known methods for the alkylation of tertiary amine groups(Menschutkin reaction) are used for the preparation of formula (I)compounds; compounds of formula (IV), wherein Ar, R, R₁, R₂ and X are asabove defined, are reacted with compounds of formula R₃Z where R₃ isdefined as above and Z is a conventional leaving group such as chloride,bromide, iodide, methanesulfonate, p-toluensulfonate or sulfate.

[0068] The alkylation reactions are normally conducted at roomtemperature, using conventional protic or aprotic preferably anhydroussolvents or their mixtures, optionally in the presence of a strongnon-nucleophilic base. Alternatively, some of compounds of formula (I)can be obtained starting from compounds of formula (IV) by reaction withMichael-type unsaturated substrates catalyzed by mineral acids such asHCl or HNO₃.

[0069] The preparation of compounds of formula (IV) is described inInternational Patent Application PCT/EP02/01974. Some of the compoundsof formula (IV) are new with respect to specific compounds described inthe above patent application, and were prepared with the methodsdescribed further below in the Preparations section.

[0070] It is understood that is the synthesis of compounds formula (I)starting from the amides of formula (IV) wherein substituents R₁ and R₂can be —H independently is included in the process. If desired, theprimary and secondary amines can be reacted in the conditions ofexhaustive alkylation with compounds of formula R₃Z to yield thecompounds of the invention of formula (I) wherein at least two of theresidues defined as R₁, R₂ and R₃ are the same. The reaction is carriedout under the same conditions as described for the conversion of theamides of formula (IV) into the compounds of the invention of formula(I).

[0071] Alternatively, the primary or secondary amides of formula (IV)can be converted into formula (I) compounds in two consecutive steps. Inthe first step of mono- or dialkylation, the reaction is carried out atroom temperature or by heating in the presence of one or two equivalentsof R₂Z alkylating agent, depending on the degree of substitution of thestarting amine group. The reactions are carried out in conventionalprotic or aprotic preferably anhydrous solvents or their mixtures,optionally in the presence of a strong non-nucleophilic base.

[0072] The compounds of the invention of formula (I) were evaluated invitro for their ability to inhibit chemotaxis of polymorphonucleateleukocytes (hereinafter referred to as PMNs) and monocytes induced bythe fractions of the complement C5a and C5a-desArg. For this purpose, toisolate the PMNs from heparinized human blood, taken from healthy adultvolunteers, mononucleates were removed by means of sedimentation ondextran (according to the procedure disclosed by W. J. Ming et al., J.Immunol., 138, 1469, 1987) and red blood cells by a hypotonic solution.The cell vitality was calculated by exclusion with Trypan blue, whilstthe ratio of the circulating polymorphonucleates was estimated on thecytocentrifugate after staining with Diff Quick.

[0073] Human recombinant fractions C5a and C5a-desArg (Sigma) were usedas stimulating agents in the chemotaxis experiments, giving practicallyidentical results.

[0074] The lyophilized C5a was dissolved in a volume of HBSS containing0.2% bovin serum albumin BSA so thus to obtain a stock solution having aconcentration of 10⁻⁵ M to be diluted in HBSS to a concentration of 10⁻⁹M, for the chemotaxis assays.

[0075] In the chemotaxis experiments, the PMNs were incubated with thecompounds of the invention of formula (I) for 15′ at 37° C. in anatmosphere containing 5% CO₂.

[0076] The chemotactic activity of the C5a was evaluated on humancirculating polymorphonucleates (PMNs) resuspended in HBSS at aconcentration of 1.5×10⁶ PMNs per mL.

[0077] During the chemotaxis assay (according to W. Falket et al., J.Immunol. Methods, 33, 239, 1980) PVP-free filters with a porosity of 5μm and microchambers suitable for replication were used.

[0078] The compounds of the invention in formula (I) were evaluated at aconcentration ranging between 10⁻⁶ and 10⁻¹⁰ M; for this purpose theywere added, at the same concentration, both to the lower pores and theupper pores of the microchamber. The wells in the lower part contain thesolution of C5a or the simple carrier, those in the upper part containthe suspension of PMNs.

[0079] Inhibition of C5a-induced chemotactic activity by the individualcompounds of the invention of formula (I) was evaluated by incubatingthe microchamber for the chemotaxis for 60 min at 37° C. in anatmosphere containing 5% CO₂.

[0080] Evaluation of the ability of the compounds of the invention offormula (I) to inhibit C5a-induced chemotaxis of human monocytes wascarried out according to the method disclosed by Van Damme J. et al.(Eur. J. Immunol., 19, 2367, 1989). Inhibition of C5a-inducedchemotactic activity by the individual compounds of the invention offormula (I) towards human monocytes was evaluated at a concentrationranging between 10⁻⁶ and 10⁻¹⁰ M by incubating the microchamber for thechemotaxis for 120 min. at 37° C. in an atmosphere containing 5% CO2.

[0081] By way of example, the inhibition data of the chemotaxis of PMN(C=10⁻⁶ M) of some representative compounds of the invention arereported in the following table: % INHIBITION COMPOUND (C = 10⁻⁶ M)(R)-(3-{2-[2-(2,6-dielorophenylamino)-phenyl]- 62 ± 3propionylamino}-propyl)-trimethylammonium iodideR(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}- 53 ± 6trimethylammonium iodide R(−)-2-(4′-isobutylphenyl)-propionylamino]-1,1-18 ± 9 dimethylpiperidinium iodideR(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}- 24 ± 41-methyl-piperidinium iodideR(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}- 57 ± 4N-cyclohexylmethyl-N,N-dimethyl-ammonium methanesulfonateR(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]- 22 ± 4propyl}-(N-benzyil)-N,N-dimethylammonium iodide

[0082] The compounds of formula (1), evaluated ex vivo in the blood intoto according to the procedure disclosed by Patrignani et al., in J.Pharmacol. Exper. Ther., 271, 1705, 1994, were found to be totallyineffective as inhibitors of cyclooxygenase (COX) enzymes.

[0083] In almost all cases, the compounds of formula (1) do notinterfere with the production of PGE₂ induced in murine macrophages bylipopolysaccharides stimulation (LPS, 1 μg/mL) at a concentrationranging between 10⁻⁵ and 10⁻⁷ M. Inhibition of the production of PGE₂which may be recorded, is mostly at the limit of statisticalsignificance, and more often is below 15-20% of the basal value.

[0084] It is therefore a further object of the present invention the useof the compounds of the invention as medicaments.

[0085] In view of the experimental evidence discussed above and of therole performed by the complement cascade, and namely its fraction C5a,in the processes that involve the activation and the infiltration ofneutrophils, the compounds of the invention are particularly useful inthe treatment of diseases such as psoriasis (R. J. Nicholoff et al., Am.J. Pathol., 138, 129, 1991), pemphigo and pemphigoid, rheumatoidarthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), intestinalchronic inflammatory pathologies such as ulcerative colitis (Y. R.Mahida et al., Clin. Sci., 82, 273, 1992), acute respiratory distresssyndrome and idiopathic fibrosis (E. J. Miller, previously cited, and P.C. Carré et al., J. Clin. Invest., 88, 1882, 1991), cystic fibrosis,chronic obstructive pulmonary disease, glomerulonephritis (T. Wada etal., J. Exp. Med., 180, 1135, 1994) and in the prevention and thetreatment of injury caused by ischemia and reperfusion.

[0086] The compounds of formula (IV) for their use as medicaments aredescribed in International Patent Application PCT/EP02/01974. The newamides of formula (IV) described below in the Preparations section havebiological activity comparable to that of amides described in the abovepatent application and can be used for the treatment of the samepathologies.

[0087] To this purpose, the compounds of the invention of formula (I)conveniently are formulated in pharmaceutical compositions usingconventional techniques and excipients such as those described in“Remington's Pharmaceutical Sciences Handbook” MACK Publishing, NewYork, 18th ed., 1990.

[0088] The compounds of the invention can be administered by intravenousinjection, as a bolus, in dermatological preparations (creams, lotions,sprays and ointments), by inhalation as well as orally in the form ofcapsules, tablets, syrup, controlled-release formulations and the like.

[0089] The average daily dose depends on several factors such as theseverity of the disease, the condition, age, sex and weight of thepatient. The dose will vary generally from 1 to 1500 mg of compounds offormula (I) per day, optionally divided in multiple administrations.Higher doses can be administered for long periods of time, thanks to thelow toxicity of compounds of the invention.

[0090] The following examples and preparations serve to illustrate theinvention.

[0091] By convention, apices (e.g. R′, S′, S″ etc.) show the absoluteconfigurations present in substituent R₁ in the compounds of theinvention of formula (I). Abbreviations: THF: tetrahydrofuran; DMF:dimethylformamide; EtAc: ethyl acetate, HOBZ: hydroxybenzotriazol,DCC:dicyclohexylcarbodiimide.

[0092] Materials and Methods

[0093] The amines used as reagents in the synthesis of compounds offormula (IV) are known products, generally commercially available orthey can be prepared according to methods described in the literature.

[0094] The synthesis of 2-aryl-propionic acids of formulaφ-Ar₃—C(CH₃)H—CO₂H and of their R-enantiomers is reported inInternational patent application PCT/EP01/01285.

[0095] The optical resolution was carried out by means of salificationwith R(+)-N-methylbenzylamine according to the method described byAkguen et al., Arzneim. Forsch., 46:9 891-894, 1996.

[0096] Preparations

[0097] Preparation of Omega-aminoalkylamides of R-2-arylpropionic acidas Intermediates

[0098] The preparation of compounds of formula (IV) is disclosed inInternational Patent application PCT/EP02/01974. Some compounds offormula (IV) are new and described for the first time in the presentpatent application.

[0099] Examples of the preparation of the new amides of formula (IV) arereported below.

[0100] Preparation 1

[0101]R(−)-2-[(3-benzoyl)phenyl]-N-[3″-(N′,N′-dimethylamino)propyl]propionamide

[0102] Hydroxybenzotriazol (0.604 g, 3.93 mmol) andN,N-dicyclohexylcarbodiimmide (0.81 g, 3.93 mmol) are added to asolution of R(−)-ketoprofen (1 g, 3.93 mmol) in anhydrousdichloromethane (25 mL). The mixture is stirred at r.t. for 30 min;N,N-dimethyl-1,3-propandiamine (0.49 mL, 3.93 mmol) is added to thesuspension formed. The resulting suspension is stirred at r.t.overnight. Dicyclohexylurea (DCU) is then filtered off under vacuum andthe filtrate is evaporated at reduced pressure; the crude oily residueis taken up in acetonitrile (20 mL) and the mixture left overnight atT=4° C. After the filtration of a further aliquot of DCU, the filtrateis again evaporated at reduced pressure and the residue is purified bymeans of flash chromatography on silica gel (eluent CHCl₃/CH₃OH 8:2);R(−)-2-[(3′-benzoyl)phenyl]-N-[3″-(N′,N′-dimethylamino)propyl]-propionamide(0.997 g, 2.94 mmol) is obtained as a transparent oil.

[0103] Yield 75%

[0104] [α]_(D)=−20 (c=0.9; CH₃OH)

[0105]¹H-NMR (CDCl₃) δ 7.90-7.40 (m, 9H); 7.25 (s, 1H, CONH); 3.65 (m,1H); 3.36 (m, 2H); 2.38 (m, 2H); 2.20 (s, 6H); 1.62 (m, 5H).

[0106] In a similar way the following compounds were also prepared:

[0107]R(−)-2-[(3′-benzoyl)phenyl]-N-(3″-N′″-piperidinopropyl)-propionamide

[0108] Yield 80%

[0109] [α]_(D)=−47.5 (c=0.3; CH₃OH)

[0110]¹H-NMR (CDCl₃) δ 7.85-7.42 (m, 9H+CONH); 3.80 (m, 1H); 3.57-3.28(m, 4H); 2.85 (m, 2H); 2.10 (m, 2H); 1.65 (m, 11H).

[0111]R(−)-2-[(4′-isobutyl)phenyl]-N-[3″-N′-(4″,4″-piperidinediol)-propyl]-propionamide

[0112] [α]_(D)=−19.5 (c=1; CH₃OH)

[0113]¹H-NMR (DMSO-d6) δ 8.05 (t, 1H, J=6 Hz, CONH); 7.25 (d, 2H, J=8Hz); 7.08 (d, 2H, J=8 Hz); 3.55 (m, 1H); 3.40 (m, 2H); 3.35-3.25 (m,6H); 2.38 (d, 2H, J=7 Hz); 2.05 (m, 4H); 1.85 (m, 1H); 1.50 (m, 2H);1.35 (d, 3H, J=7 Hz); 0.87 (d, 6H, J=7 Hz).

[0114]R(−)-2-[(4′-isobutyl)phenyl]-N-[3″-N′-(4″-carboxyamidopiperidin)-propyl]propionamide

[0115] [α]_(D)=−28.5 (c=1; CH₃OH)

[0116]¹H-NMR (DMSO-d6) δ 8.45 (d, 2H, J=8 Hz), CONH2); 8.10 (t, 1H, J=6Hz, CONH); 7.35 (d, 2H, J=8 Hz); 7.20 (d, 2H, J=8 Hz); 3.65 (m, 1H);3.42 (m, 2H); 3.15-2.90 (m, 6H); 2.35 (d, 2H, J=7 Hz); 2.15 (m, 1H);1.80 (m, 1H); 1.55 (m, 6H); 1.35 (d, 3H, J=7 Hz); 0.85 (d, 6H, J=7 Hz).

[0117]R(−)-2-[(4′-isobutyl)phenyl]-N-[4″-N,N-dimethylaminomethylphenyl]-propionamide

[0118] [α]_(D)=−35 (c=1; CH₃OH)

[0119]¹H-NMR (CDCl₃): δ 7.82 (dd, 1H, J₁=8.4 Hz, J₂=2 Hz); 7.55 (d, 1H,J=2 Hz); 7.20 (m, 2H); 7.10 (m, 2H); 6.85 (d, 2H, J=8.4 Hz); 6.15 (bs,1H, CONH); 3.70 (s, 2H); 3.50 (m, 1H); 3.20 (s, 6H); 2.45 (d, 2H, J=7Hz); 1.88 (m, 1H); 1.50 (d, 3H, J=7 Hz); 0.85 (d, 6H, J=7 Hz).

EXAMPLES

[0120] Quaternary Salts of Omega-Aminoalkylamides of R-2-Aryl-PropionicAcids

Example 1

[0121]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-1-methyl-piperidiniumiodide

[0122]R(−)-2-[(4′-isobutyl)phenyl]-N-[3″-N′-(N′-methyl)piperidinopropyl]-propionamide(0.095 g; 0.287 mmol) is dissolved in anhydrous tetrahydrofuran (6 mL)under inert atmosphere. Methyl iodide (0.1 mL, 1.61 mmol) is added tothe solution; the solution is stirred at r.t. for 18 hours until thestarting reagent is no longer detectable. The solvent is then evaporatedat reduced pressure and the residue is taken up in isopropyl ether. Awhite precipitate forms which is stirred for 6 hours. The precipitate isfiltered and dried under vacuum at T=40° C. to yield theR(−)-2-[(4′-isobutyl)phenyl]-N-[3″-N′-(N′-methyl)-piperidinopropyl]propionamideiodide (0.114 g; 0.24 mmol) as a clear yellow waxy solid.

[0123] Yield 84%

[0124] [α]_(D)=−12 (c=0.7; CH₃OH)

[0125]¹H-NMR (DMSO-d₆) δ 8.05 (t, 1H, J=6 Hz, CONH); 7.25 (d, 2H, J=8Hz); 7.08 (d, 2H, J=8 Hz); 3.55 (m, 1H); 3.25-3.02 (m, 8H); 2.90 (s,3H); 2.38 (d, 2H, J=7 Hz); 1.85-1.55 (m, 7H); 1.50 (m, 2H); 1.35 (d, 3H,J=7 Hz); 0.88 (d, 6H, J=7 Hz).

[0126] The following compounds were prepared by using the methodreported above:

[0127]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-trimetilammoniumiodide

[0128] m.p. 105-110° C.

[0129] [α]_(D)=−17 (c=1.0; CH₃OH)

[0130]¹H-NMR (CDCl₃) δ 7.42 (d, 2H, J=8 Hz); 7.20 (t, 1H, J=6 Hz, CONH);7.07 (d, 2H, J=8 Hz); 3.83 (m, 1H); 3.77 (m, 2H); 3.55-3.20 (m, 2H);3.18 (s, 9H); 2.40 (d, 2H, J=7 Hz); 2.05 (m, 2H); 1.83 (m, 1H); 1.45 (d,3H, J=7 Hz); 0.9 (d, 6H, J=7 Hz).

[0131]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-butyl}-trimethylammoniumiodide

[0132] m.p. 100-103° C.

[0133] [α]_(D)=−25 (c=1.0; CH₃OH)

[0134]¹H-NMR (CDCl₃) δ 7.25 (d, 2H, J=8 Hz); 7.09 (d, 2H, J=8 Hz); 6.18(s, 1H, CONH); 3.61 (m, 1H); 3.28 (m, 2H); 3.12 (m, 2H); 3.08 (s, 9H);2.44 (d, 2H, J=7 Hz); 1.81 (m, 1H); 1.75 (m, 4H); 1.50 (d, 3H, J=7 Hz);0.88 (d, 6H, J=7 Hz).

[0135]R(−)-2-[(4′-isobutylphenyl)-propionylamino]-1,1-dimethylpiperidiniumiodide

[0136] m.p. 80-85° C.

[0137] [α]_(D)=−7 (c=1.2; CH₃OH)

[0138]¹H-NMR (DMSO-d₆) δ 7.91 (d, 1H, J=7 Hz, CONH); 7.22 (d, 2H, J=8Hz); 7.08 (d, 2H, J=8 Hz); 3.80 (m, 1H); 3.53 (m, 1H); 3.35-3.30 (m,4H); 3.08 (s, 3H); 3.00 (s, 3H); 2.40 (d, 2H, J=7 Hz); 1.95-1.65 (m,5H); 1.3 (d, 3H, J=7 Hz); 0.87 (d, 6H, J=7 Hz).

[0139]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-4-methylmorpholiniumiodide

[0140] m.p. 84-87° C.

[0141] [α]_(D)=−17 (c=0.5; CH₃OH)

[0142] 1H-NMR (CDCl₃) δ 7.45 (d, 2H, J=8 Hz); 7.02 (m, 3H, CONH+2Har.);4.25 (m, 2H); 3.92 (m, 1H); 3.88 (m, 1H); 3.80 (m, 1H); 3.53 (m, 1H);3.35 (m, 2H); 3.15 (m, 1H); 3.00 (s, 3H); 2.92-2.70 (m, 4H); 2.40 (d,2H, J=7 Hz); 2.15 (m, 2H); 1.88 (m, 1H); 1.45 (d, 3H, J=7 Hz); 0.92 (d,6H, J=7 Hz).

[0143]R(−)-2-[(4′-isobutylphenyl)-N-(trimethylammoniumethyl)-methylamide]-propionamideiodide

[0144] m.p. 70-72° C.

[0145] [α]_(D)=−18 (c=1.0; CH₃OH)

[0146] 1H-NMR (DMSO-d₆) δ 7.22 (d, 2H, J=8 Hz); 7.11 (d, 2H, J=8 Hz);6.25 (bs, 2H, CONH); 3.57 (m, 1H); 3.30 (m, 2H); 3.10 (s, 9H); 2.45 (d,2H, J=7 Hz); 2.40 (m, 2H); 1.88 (m, 1H); 1.75 (m, 2H); 1.52 (d, 3H, J=7Hz); 0.92 (d, 6H, J=7 Hz).

[0147]R(−)-{3-[2-(3′-benzoylphenyl)-propionylamino]-propyl}-trimethylammoniumiodide

[0148] m.p. 62-65° C.

[0149] [α]_(D)=−16.3 (c=1.0; CH₃OH)

[0150]¹H-NMR (DMSO-d6) δ 8.20 (t, 1H, J=7 Hz, CONH); 7.81-7.47 (m, 9H);3.75 (m, 1H); 3.27-3.05 (m, 4H); 3.00 (s, 9H); 1.85 (m, 2H); 1.37 (d,3H, J=7 Hz).

[0151]R(−)-{3-[2-(3-benzoylphenyl)propionylamino]-propyl)]-1-methylpiperidiniumiodide

[0152] m.p. 69-73° C.

[0153] [α]_(D)=−10 (c=0.6; CH₃OH)

[0154]¹H-NMR (DMSO-d₆) δ 8.18 (t, 1H, J=7 Hz, CONH); 7.80-7.47 (m, 9H);3.70 (m, 1H); 3.28-3.05 (m, 8H); 2.92 (s, 3H); 1.87-1.53 (m, 6H); 1.42(m, 2H); 1.38 (d, 3H, J=7 Hz).

[0155](R)-{3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-propionylamino}-propyl)-trimethylammoniumiodide

[0156] [α]_(D)=−15 (c=1.0; CH₃OH)

[0157]¹H-NMR (DMSO-d₆) δ 8.48 (m, 1H, CONH); 8.27 (s, 1H, NH); 7.52 (d,2H, J=8 Hz); 7.18 (q, 2H, J₁=8 Hz, J₂=16 Hz); 7.05 (t, 1H, J=7 Hz); 6.88(t, 1H, J=7 Hz); 6.30 (d, 1H, J=8 Hz); 3.75 (m, 1H); 3.30 (m, 11H); 3.21(m, 2H); 1.88 (m, 2H); 1.64 (d, 3H, J=7 Hz).

[0158] (2R),(4″S)1-{4-carboxy-4-[2-(4-isobutyl-phenyl)-propionylamino]-butyl}-1-methyl-piperidiniumiodide

[0159] [α]_(D)=−9.5 (c=1.0; CH₃OH)

[0160]¹H-NMR (DMSO-d₆): δ 8.66 (bs, 1H, CONH); 7.22 (d, 2H, J=8 Hz); 7.5(d, 2H, J=8 Hz); 4.00 (m, 1H); 3.80 (m, 1H); 2.95 (m, 6H); 2.90 (s, 3H);2.45 (d, 2H, J=7 Hz); 1.82 (m, 1H); 1.70-1.33 (m, 10H); 1.31 (d, 3H, J=7Hz); 0.89 (d, 6H, J=7 Hz).

[0161](2R)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(1″-methyl-4″carbonyl)-piperidiniumiodide

[0162] [α]_(D)=−39 (c=1; CH₃OH)

[0163]¹H-NMR (DMSO-d6) δ 8.15 (t, 1H, J=6 Hz, CONH); 7.28 (d, 2H, J=8Hz); 7.12 (d, 2H, J=8 Hz); 3.80 (m, 1H); 3.70 (m, 2H); 3.35-3.25 (m,6H); 3.18 (s, 3H); 2.35 (d, 2H, J=7 Hz); 2.12 (m, 4H); 1.85 (m, 1H);1.50 (m, 2H); 1.37 (d, 3H, J=7 Hz); 0.87 (d, 6H, J=7 Hz).

[0164]2R-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(1″-methyl-4″-carboxyamide)-piperidiniumiodide

[0165] [α]_(D)=−25 (c=1; CH₃OH)

[0166]¹H-NMR (DMSO-d6) δ 8.74 (d, 2H, J=8 Hz, CONH2); 8.18 (t, 1H, J=6Hz, CONH); 7.30 (d, 2H, J=8 Hz); 7.22 (d, 2H, J=8 Hz); 3.75 (m, 1H);3.45 (m, 2H); 3.35 (s, 3H); 3.20-3.00 (m, 6H); 2.38 (d, 2H, J=7 Hz);2.15 (m, 1H); 1.90 (m, 1H); 1.75 (m, 6H); 1.35 (d, 3H, J=7 Hz); 0.85 (d,6H, J=7 Hz).

[0167]R(−)-2-[(4′-isobutyl)-phenyl]-N-[4″-N,N,N-trimethylaminomethylphenyl]-propionamideiodide

[0168] [α]_(D)=−23 (c=1; CH₃OH)

[0169]¹H-NMR (DMSO-d₆): δ 7.80 (dd, 1H, J₁=8.4 Hz, J₂=2 Hz); 7.55 (d,1H, J=2 Hz); 7.24 (m, 2H); 7.10 (m, 2H); 7.00 (d, 2H, J=8.4 Hz); 6.20(bs, 1H, CONH); 3.70 (s, 2H); 3.50 (m, 1H); 3.20 (s, 9H); 2.45 (d, 2H,J=7 Hz); 1.88 (m, 1H); 1.50 (d, 3H, J=7 Hz); 0.85 (d, 6H, J=7 Hz).

Example 2

[0170] The following compound was prepared according to the methoddescribed in Example 1, but using ethyliodide as the reagent:

[0171] R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}triethylammonium iodide

[0172] m.p. 100-102° C.

[0173] [α]_(D)=−19.5 (c=1.0; CH₃OH)

[0174]¹H-NMR (CDCl₃) δ 7.43 (d, 2H, J=8 Hz); 7.22 (t, 1H, J=6 Hz, CONH);7.10 (d, 2H, J=8 Hz); 3.83 (m, 1H); 3.77 (m, 2H); 3.55-3.35 (m, 2H);3.15 (q, 6H, J=7 Hz); 2.95 (t, 9H, J=7 Hz); 2.42 (d, 2H, J=7 Hz); 2.05(m, 2H); 1.85 (m, 1H); 1.45 (d, 3H, J=7 Hz); 0.9 (d, 6H, J=7 Hz).

Example 3

[0175] The following compound was prepared according to the methoddescribed in Example 1, but using benzyliodide as the reagent:

[0176]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(N-benzyl)-N,N-dimethylammoniumiodide

[0177] m.p. 97-100° C.

[0178] [α]_(D)=−12 (c=1.0; CH₃OH)

[0179]¹H-NMR (CDCl₃) δ 7.42 (d, 2H, J=8 Hz); 7.30-7.25 (m, 5H); 7.20 (t,1H, J=6 Hz, CONH); 7.07 (d, 2H, J=8 Hz); 3.85 (m, 1H); 3.72 (m, 2H);3.68 (s, 2H); 3.55-3.32 (m, 2H); 3.20 (s, 6H); 2.40 (d, 2H, J=7 Hz);2.05 (m, 2H); 1.83 (m, 1H); 1.45 (d, 3H, J=7 Hz); 0.9 (d, 6H, J=7 Hz).

Example 4

[0180] The following compound was prepared according to the methoddescribed in Example 1, but using cyclohexylmethyl metanesulfonate asthe reagent:

[0181]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-N-cyclohexylmethyl-N,N-dimethyl-ammoniummetaneosulfonate

[0182] [α]_(D)=−23 (c=1.0; CH₃OH)

[0183]¹H-NMR (DMSO-d₆) δ 7.44 (d, 2H, J=8 Hz); 7.20 (t, 1H, J=6 Hz,CONH); 7.08 (d, 2H, J=8 Hz); 3.83 (m, 1H); 3.77 (m, 2H); 3.55-3.20 (m,4H); 3.18 (s, 6H); 3.00 (s, 3H); 2.40 (d, 2H, J=7 Hz); 2.05 (m, 2H);1.83 (m, 1H); 1.75 (m, 5H); 1.48 (m, 1H); 1.45 (d, 3H, J=7 Hz); 1.22 (m,3H); 0.95 (m, 2H); 0.9 (d, 6H, J=7 Hz).

Example 5

[0184] The following compound was prepared according to the methoddescribed in Example 1, but using allyl bromide in lieu of methyl iodide

[0185]R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-1-allylpiperidiniumbromide

[0186] [α]_(D)=−14.5 (c=0.5; CH₃OH)

[0187]¹H-NMR (DMSO-d6) δ 8.05 (t, 1H, J=6 Hz, CONH); 7.25 (d, 2H, J=8Hz); 7.08 (d, 2H, J=8 Hz); 6.05 (m, 1H); 5.35 (d, 1H, J=2 Hz); 5.15 (d,1H, J=2 Hz); 3.80 (d, 2H, J=7 Hz); 3.55 (m, 1H); 3.25-3.02 (m, 8H); 2.38(d, 2H, J=7 Hz); 1.85-1.55 (m, 7H); 1.50 (m, 2H); 1.35 (d, 3H, J=7 Hz);0.88 (d, 6H, J=7 Hz).

Example 6

[0188] The following compound was prepared starting from the(4-aminophenyl)trimethylammonium iodide hydrochloride (commercialreagent):

[0189]R(−)-2-[(4′-isobutyl)phenyl]-N-[4″-NNN-trimethylaminophenyl]-propionamideiodide

[0190] Hydroxybenzotriazol (0.62 g; 4.58 mmol) is added, at T=0° C., toa solution of (R)(−)Ibuprofen (1.01 g; 5 mmol) in DMF (4.5 mL). Thesolution is stirred at T=0° C. for 30 min;(4-aminophenyl)-trimethylammonium iodide hydrochloride (1.433 g; 4.56mmol) is then added to the mixture. N,N-dicyclohexylcarbodiimmide (1.02g; 4.95 mmol) is added gradually in small portions. After stirring atT=0° C. for 2 h., the mixture is left to warm to r.t. Then it is stirredfor 24 h. The DCU which is formed is filtered off and DMF is distilledoff under reduced pressure. The residue is dissolved in H₂O and stirredin diisopropyl ether (30 mL) overnight at room temperature; theprecipitate formed is filtered under vacuum and dried in oven at T=40°C. for 6 h, yielding a white solid (1.67 g; 3.58 mmol);

[0191] [a]_(D)=−31 (c=1; CH₃OH)

[0192]¹H-NMR (DMSO-d₆): δ 7.85 (dd, 1H, J₁=8.4 Hz, J₂=2 Hz); 7.62 (d,1H, J=2 Hz); 7.24 (m, 2H); 7.10 (m, 2H); 7.02 (d, 2H, J=8.4 Hz); 6.15(bs, 1H, CONH); 3.50 (m, 1H); 3.25 (s, 9H); 2.45 (d, 2H, J=7 Hz); 1.85(m, 1H); 1.52 (d, 3H, J=7 Hz); 0.90 (d, 6H, J=7 Hz).

1. A (R)-2-aryl-propionamide compound of formula (I):

wherein Ar represents a substituted or non-substituted aryl group; Rrepresents hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,optionally substituted by a CO₂R₄ group, wherein R₄ represents hydrogenor a linear or branched C₁-C₆ alkyl group or a linear or branched C₂-C₆alkenyl group; X represents: linear or branched C₁-C₆ alkylene, C₄-C₆alkenylene, C₄-C₆ alkynylene, optionally substituted by a CO₂R₄ group orby a CONHR₅ group wherein R₅ represents hydrogen, linear or branchedC₂-C₆ alkyl or an OR₄ group, R₄ being defined as above; phenyl or aphenylmethylene group of formula:

a (CH₂)_(m)-B-(CH₂)_(n), group, optionally substituted by a CO₂R₄ orCONHR₅ group, as defined above, wherein B is an oxygen or sulfur atom, mis zero or an integer from 2 to 3 and n is an integer from 2 to 3; or Bis a CO, SO or CONH group, m is an integer from 1 to 3 and n is aninteger from 2 to 3; or X together with the nitrogen atom to which it isbound and with the R₁ group forms a nitrogen containing 3-7 memberedheterocyclic monocyclic or polycyclic ring; R₁, R₂ and R₃ areindependently linear or branched C₁-C₆ alkyl, optionally substituted byan oxygen or sulfur atom, a C₃-C₇ cycloalkyl, C₃-C₆ alkenyl,C₃-C₆-alkynyl, aryl, aryl-C₁-C₃-alkyl, hydroxy-C₂-C₃-alkyl group; or R₁and R₂ together with the N atom to which they are bound, form a nitrogencontaining 3-7 membered heterocyclic ring of formula (II) and R₃independently has the meanings as defined above,

wherein Y represents a single bond, a methylene group, an oxygen atom, anitrogen atom or a sulfur atom and p represents an integer from 0 to 3;Z⁻ represents a pharmaceutically acceptable counter-ion of quaternaryammonium salts, with the proviso that when Ar is biphenyl, R₂ and R₃ arenot ethyl.
 2. The compound according to claim 1, wherein Ar is selectedfrom a) an Ar_(a) mono- or poly-substituted aryl group of (±)2-aryl-propionic acids selected in the group consisting of alminoprofen,benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, loxoprofen, R-naproxen, pirprofen and itsdehydro and dihydro derivatives, pranoprofen, surprofen, tiaprofenicacid, zaltoprofen; b) an aryl-hydroxymethyl-aryl group of formula (IIIa)both as diastereoisomer mixture, or as single diastereoisomers,

 wherein, when Ar₂ is phenyl Ar₁ is selected from the group consistingof phenyl and thien-2-yl while when Ar₁ is phenyl, Ar₂ is selected fromthe group consisting of phenyl, 4-thienyl, pyridyl. c) an aryl offormula (IIIb):

wherein: Ar_(b) is a phenyl mono- or poly-substituted by hydroxy,mercapto, C₁-C₃-alcoxy, C₁-C₃-alkylthio, chlorine, fluorine,trifluoromethyl, nitro, amino, optionally substituted C₁-C₇-acylamino; Φis hydrogen; a linear or branched C₁-C₅ alkyl, C₂-C₅-alkenyl orC₂-C₅-alkynyl residue optionally substituted by C₁-C₃-alkoxycarbonyl,substituted or non-substituted phenyl, 2-, 3- or 4-pyridyl,quinolin-2-yl; a C₃-C₆-cycloalkyl; 2-furyl; 3-tetrahydrofuryl;2-thiophenyl; 2-tetrahydrothiophenyl or a a C₁-C₈-(alkanoyl,cycloalkanoyl, arylalkanoyl)-C₁-C₅-alkylamino group e.g.acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino; and d) a2-(phenylamino)-phenyl of formula (III c):

 wherein the substituents P₁ and P₂ indicate that the two phenyl groupsbear, each independently, mono- or poly-substitutions with C₁-C₄-alkyl,C₁-C₃-alcoxy groups, chlorine, fluorine and/or trifluoromethyl.
 3. Thecompound according to any one of claims 1 and 2 wherein: R is hydrogen;X is: a linear C₁-C₆ alkylene, preferably C₂-C₄, optionally substitutedat C₁ by a —CO₂R₄ group as defined above; a linear C₁-C₆ alkyleneoptionally substituted at C₁ by a —CONHR₅ group wherein R₅ is OH;2-butynylene, cis-2-butenylene, trans-2-butenylene; 3-oxa-pentylene,3-thio-pentylene, 3-oxa-hexylene, 3-thio-hexylene;(CH₂)_(m)—CO—NH—(CH₂)_(n)— wherein m and n are each independently aninteger from 2 to 3; (CHR′)—CONH—(CH₂)_(n) wherein n is an integer from2 to 3 and R′ is a methyl, having absolute configuration R or S; aphenyl or phenylmethylene group of formula:

or X, together with the N atom, form an azocycloaliphatic ring.
 4. Thecompound according to claim 3, wherein X is a linear C₂-C₄ alkylene. 5.The compound according to any one of claims 1 and 2, wherein NR₁R₂R₃group represents a trimethylammonium, triethylammonium,N-methyl-N,N-diethylammonium, N-methyl-N,N-diisopropylammonium,N-cyclohexylmethyl-N,N-dimethylammonium,N-cyclopentylamino-N,N-dimethylammonium, N-methyl-1-piperidinium,N-ethyl-1-piperidinium, N-methyl-4-morpholinium, N-methyl-4thiomorpholinium, N-benzyl-N,N-dimethylammonium, N-allyl-1-piperidinium,4-oxy-N-methyl-piperidinium group or X together with the amine N towhich it is bound and with the R₁ group, forms a nitrogen containing 5-6membered heterocyclic ring and the substituents R₂ and R₃ representindependently a methyl or cyclohexyl residue.
 6. The compound accordingto any one of claims 1 and 2, wherein Ar is selected from4-isobutylphenyl, 4-cyclohexylmethylphenyl, 4-(2-methyl) allyl-phenyl,3-phenoxyphenyl, 3-benzoyl-phenyl, 3-acetyl-phenyl, the single (R) (S)diastereoisomers and the diastereoisomeric (R,S) mixture of3-C₆H₅—CH(OH)-phenyl, 3-CH₃—CH(OH)-phenyl, 5-C₆H₅—CH(OH)-thienyl,4-thienyl-CH(OH)-phenyl, 3-(pyrid-3-yl)-CH(OH)-phenyl,5-benzoyl-thien-2-yl, 4-thienoyl-phenyl, 3-nicotinoyl-phenyl,2-fluoro-4-phenyl, 6-metoxy-2-naphthyl, 5-benzoyl-2-acetoxy-phenyl,5-benzoyl-2-hydroxy-phenyl, 4-cyclopentyl-phenyl,4-(2-oxo-cyclopentyl)-phenyl, 4-(2-oxo-cyclohexyl)-phenyl.
 7. Thecompound according to claim 1, wherein Ar is a phenyl group3-substituted by isoprop-1-en-1-yl-isopropyl, pent-2-en-3-yl, pent-3-yl;1-phenylethylen-1-yl; α-methylbenzyl.
 8. The compound according to claim1, wherein the Ar groups in the formula (IIIc) are2-(2,6-dichloro-phenyl-amino)-phenyl;2-(2,6-dichlorophenyl-amino)-5-chloro-phenyl;2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl;2-(3-trifluoromethyl-phenylamino)-phenyl.
 9. The compound according toclaim 1, wherein Z⁻ is a halide chosen from Cl⁻, I⁻, Br⁻, a sulfateanion, methanesulfonate or p-toluenesulfonate.
 10. The compoundaccording to claim 1, selected from:(R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-trimethylammoniumiodide;(R)-{3-[2-(3-benzoylphenyl)-propionylamino]propyl}-trimethylammoniumiodide;(R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-N-ethyl-N,N-dimethylammoniumiodide;(R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-N-cyclohexylmethyl-N,N-dimethylammoniumiodide;(R)-{3-[2-(4-cyclopentylmethylphenyl)-propionylamino]propyl}-trimethylammoniumiodide;(R)-{3-[2-(3-benzoylphenyl)-propionylamino]propyl}-N-isopropyl-N,N-dimethylammoniumiodide;(R)-{3-[2-(4-isobutylphenyl)-propionylamino]butyl-trimethylammoniumiodide;(R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-1-methyl-piperidiniumiodide; (R)-{3-[2-(3-benzoylphenyl)-propionylamino]propyl}-1-methylpiperidinium iodide;(R)-{3-[2-(4-isobutylphenyl)-propionylamino]propyl}-4-methyl-morpholiniumiodide;(R)-{3-[2-(3-isopropylphenyl)-propionylamino]propyl}-4-methyl-thiomorpholiniummethanesulfonate;(R)-{3-[2-(4-isobutylphenyl)-propionylamino]ethyl-trimethylammoniumbromide;(R)-2-[(4-isobutylphenyl)-propionylamino]-1,1-dimethyl)piperidiniump-toluenesulfonate;(R),(S′)-2-(4-isobutylphenyl)-N-[(1-carboxy-2″-N,N,N-trimethylammonium)ethyl]propionamidemethanesulfonate; R(−)-2-[(4-isobutylphenyl)-N-(trimethylammoniumethyl)methylamide]propionamide iodide;(R)(3-{2-[2(2,6-dichlorophenylamino)-phenyl]-propionylamino}-propyl)-trimethylammoniummethanesulfonate;(2R),(4″S)1-{4-carboxy-4-[2-(4-isobutyl-phenyl)-propionylamino]butyl}-1-methyl-piperidiniumiodide;R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(N-benzyl)-N,N-dimethylammoniumiodide; 2R-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(1″methyl-4″carboxyamide) piperidinium iodide;(2R)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-(1″-methyl-4″carbonyl) piperidinium iodide;R(−)-{3,-[-(4′-isobutylphenyl)-propionylamino]-propyl}-triethylammoniumiodide;R(−)-{3-[2-(4′-isobutylphenyl)-propionylamino]-propyl}-1-allylpiperidiniumbromide; R(−)-2-[(4′-isobutyl)phenyl]-N-[4″-N,N,N-trimethylaminophenyl]propionamide iodide; andR(−)-2-[(4′-isobutyl)phenyl]-N-[4″-N,N,N-trimethylaminomethylphenyl]propionamideiodide.
 11. A medicament comprising the compound according to claim 1.12. A method for inhibiting chemotaxis of neutrophils and monocytesinduced by C5a in a subject in need thereof, comprising the step ofadministering the compound according to claim 1 to said subject, whereinsaid compound inhibits chemotaxis of neutrophils and monocytes inducedby C5a.
 13. A method for treating psoriasis, pemphigus and pemphigoid,rheumatoid arthritis, intestinal chronic inflammatory pathologiesincluding ulcerative colitis, acute respiratory distress syndrome,idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonarydisease and/or glomerulonephritis in a subject in need thereof,comprising the step of administering the compound according to claim 1to said subject.
 14. A method for preventing or treating an injurycaused by ischemia and reperfusion in a subject in need thereof,comprising the step of administering the compound according to claim 1to said subject.
 15. Pharmaceutical compositions containing a compoundaccording to claim 1 in admixture with a suitable carrier thereof.
 16. Aprocess for the preparation of a (R)-2-aryl-propionamide compound offormula (I):

wherein Ar, X, R₁, R₂, R₃ have the meaning as defined in claim 1,comprising reacting amides of formula (IV)

with compounds of formula R₃Z, wherein Z is a conventional leavinggroup.
 17. (Canceled).
 18. The process according to claim 16, whereinthe conventional leaving group is selected from the group consisting ofchloride, bromide, iodide, methanesulfonate, p-toluensulfonate, andsulfate.